One goal of cancer immunotherapy is to identify antigens that are either uniquely expressed on tumor cells and/or are overexpressed (Carter et al Endocrine-Related Cancer, 2004, 11:659). The antigens exhibiting these properties can then be used as targets of antibodies elicited by vaccination or monoclonal antibodies and antibody conjugates administered therapeutically. Antibodies that are reactive with antigens that are uniquely expressed or are relatively overexpressed in cancer cells can limit growth and/or metastasis of the cells. The mechanisms include antibody dependent cellular cytotoxicity (ADCC), antibody dependent cytotoxicity (ADC), or complement-dependent cytotoxicity (CDC) (Carter et al Endocrine-Related Cancer, 2004, 11:659). Further, antibodies that are reactive with cell surface antigens can be internalized after binding to the cell surface antigen by endocytosis. Thus, attachment of cytotoxic drugs or toxins to the antibody can provide a means to specifically target the reagents to cancer cells.
Many human tumors have been shown to uniquely express or overexpress a derivative of poly alpha (2→8) N-acetyl neuraminic acid that contains de-N-acetyl residues using a murine monoclonal antibody, SEAM 3 (Moe et al, Infect. Immun., 2005, 73:2123). SEAM 3 binds to poly alpha (2→8) N-acetyl neuraminic acid that contains a mixture of N-acetyl and de-N-acetyl residues. SEAM 3 can be used to detect expression of this antigen both intracellularly and on the cell surface and has functional activity against tumor cells that express the antigen.
Sialic acids are N- and/or O-substituted derivatives of the nine carbon acidic sugar, neuraminic acid (Varki, A. Glycobiology, 1992, 2:25). In humans, the sugars are located on the terminal ends of a wide variety of cell surface glycoproteins and glycolipids and have an important role in many biological processes. In cancer, cells that can metastasize often have larger amounts of sialic acid-modified glycoproteins, which may help them enter the blood stream. Also, it has long been recognized that the sialic acid of tumor cells is modified in ways that differ from normal cells (Hakamori Cancer Res. 1996, 56:5309, Dall'Olio Clin. Mol. Pathol. 1996, 49:M126, Kim and Varki Glycoconj. J. 1997, 14:569). For instance, altered expression patterns of sialic acid and its derivatives have been used as markers for abnormal cellular processes such as cancer. (O'Kennedy et al., Cancer Lett., 1991 58:91; Vedralova et al. Cancer Lett. 1994 78:171; and Horgan et al., Clin. Chim. Acta., 1982 118:327; and Narayanan, S. Ann. Clin. Lab. Sci. 1994 24:376).
One sialic acid derivative thought to be uncommon in normal cells, but present on cancer cells is de-N-acetyl sialic acid (Hanai et al J. Biol. Chem. 1988, 263:6296, Manzi et al J. Biol. Chem. 1990, 265:1309, Sjoberg et al J. Biol. Chem. 1995, 270:2921, Chamas et al 1999, Cancer Res. 59:1337; and Popa et al Glycobiology. 2007 17:367).
Sialic acid derivatives that are recognized by specific antibodies and the level of expression of the derivative can be manipulated both in vitro and in vivo. Most often, the expression of a particular sialic acid derivative in human cells has been manipulated by providing derivatives of mannosamine (Bertozzi et al., “Chemical Glycobiology” Science (2001) 291:2357-2364). For example, it has been shown that providing exogenous N-propionyl mannosamine results in the production of N-propionyl polysialic acid (N—Pr PSA) derivatives that can be detected by anti-N—Pr PSA monoclonal antibodies and polyclonal antibodies elicited by immunization with an N—Pr PSA-tetanus toxoid conjugate vaccine (Zou et al J. Biol. Chem., 2004, 279:25390).
It has also been shown that eukaryotic cells can compensate for a block of internal sialic acid biosynthesis by acquiring another precursor of sialic acid biosynthesis, N-acetyl neuraminic acid, from extracellular sources (Oetke et al, Eur. J. Biochem., 2001, 268:4553). Cells also can acquire sialic acid derivatives, such as N-glycoyl sialic acid, from N-glycoyl sialic acid-containing glycoconjugates by pinocytosis (Bardor et al, J. Biol. Chem., 2006, 280:4228). It has been suggested that the sialic acid present on internalized glycoconjugates is hydrolyzed to N-acyl neuraminic acid when endocytotic vesicles fuse with lysozomes. The free N-acyl neuraminic acid is then transported first to the cytoplasm then to the nucleus by specific transport proteins where it is finally converted to the sialic acid transferase substrate, CMP-N-acyl neuraminic acid (Bardor et al, J. Biol. Chem., 2006, 280:4228).
Literature
Amino sugars, derivatives and related literature of interest are reported in the following U.S. Pat. Nos. 4,021,542; 4,062,950; 4,175,123; 4,216,208; 4,254,256; 4,314,999; 4,656,159; 4,713,374; 4,797,477; 4,803,303; 4,840,941; 4,914,195; 4,968,786; 4,983,725; 5,231,177; 5,243,035; 5,264,424; 5,272,138; 5,332,756; 5,667,285; 5,674,988; 5,759,823; 5,962,434; 6,075,134; 6,110,897; 6,274,568; 6,407,072; 6,458,937; 6,548,476; 6,697,251; 6,680,054; 6,936,701; and 7,070,801, and in the following references: Angata and Varki Chem. Rev. 2002, 102:439; Hakamori Cancer Res. 1996, 56:5309; Dall'Olio Clin. Mol. Pathol. 1996, 49:M126; Kim and Varki Glycoconj. J. 1997, 14:569; Hanai et al J. Biol. Chem. 1988, 263:6296; Manzi et al J. Biol. Chem. 1990, 265:1309; Sjoberg et al J. Biol. Chem. 1995, 270:2921; Chamas et al Cancer Res. 1999, 59:1337; Popa et al Glycobiology. 2007 17:367; Kayser et al J. Biol. Chem. 1992 267:16934; Keppler et al Glycobiology 2001, 11:11R; Luchansky et al Meth. Enzymol. 2003, 362:249; Oetke et al Eur. J. Biochem. 2001, 268:4553; Collins et al Glycobiology 2000, 10:11; and Bardor et al J. Biol. Chem. 2005, 280:4228.
The antibody SEAM 3 is reported in Moe et al, Infect. Immun., 2005, 73:2123. Sodium borohydride reactions and related are reported in various references, such as Hirano et al, Connect Tissue Res, 1975, 3:73; Shimamura et al, Arch Biochem Biophys, 1984, 232:699; and Djanashvili et al, Chem Eur J, 2005, 11:4010.
Various references report on sialic acid precursors, derivatives, antigens and uses (Zou et al J. Biol. Chem., 2004, 279:25390; Oetke et al Eur. J. Biochem., 2001, 268:4553; Bardor et al, J. Biol. Chem., 2006, 280:4228; Bertozzi et al., “Chemical Glycobiology” Science (2001) 291:2357-2364). See also US 2007/0010482; U.S. application Ser. No. 11/645,255, filed Dec. 22, 2006; WO 2006/002402; and PCT application serial no. PCT/US2006/04885, filed Dec. 22, 2006.